The Penn Center for the Study of Epigenetics in Reproduction (PennCSER) will elucidate epigenetic mechanisms that govern male and female reproduction, contribute to male infertility and impact development of mouse and human concepti conceived through assisted reproductive technologies (ART). The PennCSER centerpiece is 4 integrated, innovative research projects, spearheaded by experienced leaders in the areas of epigenetics and reproduction. The Center also features an Outreach program that has been in place for more than 5 years; the Penn Academy of Reproductive Sciences uses hands on laboratory experiences and interactive lectures to educate high school students, largely from the Philadelphia area schools, in the reproductive sciences. The clinical project (Project 1, Coutifaris, Sapienza, Mainigi and Senapati) will assess the impact of the periconceptional maternal environment on DNA methylation and gene expression in embryonic (placental vessels and endothelial cells) and extra-embryonic (trophoblasts) tissues in IVF pregnancies following fresh or frozen transfer, pregnancies resulting from unassisted conception and pregnancies following trophectoderm biopsy for pre-implantation genetic testing for aneuploidy (PGT-A). This project will also determine the stability of epigenetic signatures determined at birth into childhood and correlate them with the children?s growth phenotype. Project 2 (Bartolomei, Mainigi, Schultz) will closely parallel Project 1 using a validated mouse model to study the effect of ART laboratory manipulations on epigenetic gene regulation and physiological outcomes in term conceptuses and adults. Project 2 will address the question of whether embryo freezing and transfer to an unstimulated uterus is optimal and evaluate the safety and outcomes associated with trophectoderm biopsy. Project 2 will also test whether decreased expression of Grb10, a growth-regulatory imprinted gene overexpressed in human and mouse ART-derived conceptuses, can rescue ART-associated phenotypes in a mouse model. Project 3 (Berger) will investigate histone modifications during mouse spermatogenesis and determine their conservation in normal human sperm and disruption in abnormal human sperm, as well as in mouse models exhibiting abnormal histone retention. Project 4 (Wang and Masson) will examine the function of TEX15, a protein that is required for meiosis and male fertility, and is a novel epigenetic regulator essential for retrotransposon silencing. Project 4 will also determine whether aberrant retrotransposon activity is associated with male infertility. PennCSER will not only provide training to clinicians, physician scientists, and basic research fellows in the area of epigenetics but also provide PennCSER?s expertise to the NCTRI and associated program members.